1. Field of the Invention
The present invention relates to the improvement of oral transmucosal drug delivery systems. In particular, the invention relates to solid pharmaceutical dosage forms for oral transmucosal delivery of pharmaceutically active substances, and more particularly, to solid dosage forms producing higher dissolution rates and accordingly, higher absorption rates of the pharmaceutically active substance. Furthermore, the present invention provides improved solubility in saliva and mucosal absorption without compromising stability of the solid dosage form during storage.
2. Description of the Prior Art
Solid pharmaceutical dosage forms are well known in the art. Compared to other dosage forms, such as solutions (oral or injection) and vapor or gas inhalation, the oral solid dosage forms are the most preferred dosage forms and they account for eighty percent of all the pharmaceutical products on the market. Solid dosage forms are easier for patient or caregiver to identify, handle and administer. They are also non-invasive and have high patient compliance.
With respect to drug delivery routes, solid dosage forms can be further divided into several groups, gastrointestinal (GI) tract delivery, suppository (rectal, vaginal and urethral) delivery and oral transmucosal delivery. The majority of solid dosage forms on the market are designed for gastro-intestinal delivery. GI delivery is often referred to simply as "oral delivery." Solids are also commonly delivered as suppositories such as laxatives, contraceptives and hemorrhoid medication. Relatively few drug formulations are designed as solid dosage forms intended to deliver a drug through the oral mucosa. Two such drug formulations are Oralet (.RTM.) and Actiq(.RTM.).
Despite the overall popularity of other delivery methods, oral transmucosal (OT) delivery is a particularly advantageous delivery route. One of the advantages of OT delivery is that it is a non-invasive drug delivery method. Furthermore, OT delivery has better patient compliance, less risk of infection and lower cost than invasive procedures such as injection and implantation. It also has much shorter onset time, i.e., the time from administration to therapeutic effect, than does oral delivery. A drug absorbed via the oral mucosa will also avoid first pass metabolism, in which the drug is metabolized in the GI tract and liver. Oral transmucosal delivery is simple and can be administered by the caregiver or the patient with minimal discomfort.
Various solid dosage forms, such as sublingual tablets, troches, lozenges, lozenges-on-a-stick, chewing gums, and buccal patches, have been used to deliver drugs via the oral mucosal tissue. U.S. Pat. No. 5,711,961 to Reiner, et al. discloses a chewing gum for the delivery of pharmaceuticals. The chewing gum delivery dosage form of Reiner is primarily directed for patients who may be more disposed to self-administer a drug in chewing gum form as opposed to other less familiar dosage forms. The gum may also be used to mask the taste of various pharmaceutical ingredients. Reiner also discloses the use of the gum formulation to extend the duration of drug delivery.
Transmucosal delivery of drugs is also accomplished through the use of patches which are attached using an adhesive to mucosal surfaces in the oral cavity. Oral transmucosal delivery using a buccal patch is disclosed in U.S. Pat. No. 5,298,256 to Flockhart, et al. The buccal patch may be designed as a "closed" delivery system, that is, the environmental conditions inside the patch are primarily controlled by the formulation. Employing a closed delivery system can facilitate drug delivery, such as allowing the use of enhancers or other permeability facilitators in the formulation which might otherwise be impractical. In an "open" delivery system, such as lozenges or sublingual tablets, the drug delivery conditions are influenced by the conditions of the surrounding environment, such as rate of saliva secretion, pH of the saliva, or other conditions beyond the control of the formulation. Buccal patch delivery also displays a pharmacokinetic delivery profile that can mimic a short term IV infusion.
Solid dosage forms such as lozenges and tablets are commonly used for oral transmucosal delivery of pharmaceuticals. For example, nitroglycerin sublingual tablets have been on the market for many years. The sublingual tablets are designed to deliver small amounts of the potent nitroglycerin, which is almost immediately dissolved and absorbed. On the other hand, most lozenges or tablets are typically designed to dissolve in the mouth over a period of at least several minutes which allows extended dissolution of the lozenge and absorption of the drug.
A lozenge-on-a-stick dosage form of transmucosal drug delivery is disclosed in U.S. Pat. No. 4,671,953 to Stanley, et al. In addition to being non-invasive and providing a particularly easy method of delivery, the lozenge-on-a-stick dosage form allows a patient or caregiver to move the dose in and out of the mouth to titrate the dose. This practice is called dose-to-effect, in which a patient or caregiver controls the administration of the dose until the expected therapeutic effect is achieved. This is particularly important for certain symptoms, such as pain, nausea, motion sickness, and premedication prior to anesthesia because each patient needs a different amount of medication to treat these symptoms. For these types of treatments, the patient is the only one who knows how much medication is enough. Once the appropriate amount of drug is delivered, the patient or caregiver can remove the lozenge, thus, stopping the drug delivery to prevent overdose.
Solid dosage units are made in a number of ways. In a high volume manufacturing facility, solid dosage units can be made by direct compression, injection molding, freeze-drying or other solid processing techniques. Compression, by far, is the most commonly used manufacturing process in making solid dosage units. A typical formulation of solid dosage form consists of active ingredient(s), bulking agent(s), binder(s), flavor(s), lubricant(s) and other excipients.
To benefit from the advantages of oral transmucosal delivery, solid dosage forms must be formulated to take into account the oral cavity's unique environment. In certain aspects, the unique environment of the oral cavity can complicate the transmucosal delivery of the drug. For example, one of the significant aspects of the oral cavity environment with regard to its use as a drug administration route is that there is relatively little solvent into which a solid dosage form can dissolve. Furthermore, the relative amounts of saliva produced in given circumstances can vary widely. On the average, salivary glands produce between 800 to 1500 ml saliva a day. In a resting, unstimulated state, salivary glands produce about 0.5 ml mucous-type saliva per minute, while stimulated salivary glands produce about 1 to 3 ml per minute. During the time required for solid dose drug delivery, about 10 to 15 minutes, the total amount of saliva produced is 10 to 15 ml, which is a small volume compared to 600 to 1000 ml of potential solvent produced in the GI tract.
Similarly, there is a limited period of time during which the solid dosage form can be dissolved and absorbed. An orally (GI tract) delivered solid dose will remain in the GI tract 8 for several hours. An oral transmucosal dose remains in the oral cavity for a mere 10 to 15 minutes. During this period, the solid unit has to be dissolved, and the drug must be released and absorbed. This is a major challenge for formulating the transmucosal solid dosage form.
The absorption of a drug across the mucosal tissue can be described using the equation of Fick's first law: ##EQU1##
where dA is the amount of drug delivered over time dt, K.sub.p is the partition coefficient of the drug between oral mucosal tissue and the drug solution, D is the diffusion coefficient of the drug inside the oral mucosal tissue, S is the surface area of the oral cavity, h is the thickness of the oral mucosal tissue, C.sub.1 and C.sub.2 are the drug concentrations in the solution and blood circulation, respectively.
The capacity of the oral transmucosal delivery is limited in large part by the surface area available for drug absorption. The surface area in the oral cavity is 200 cm.sup.2, which is relatively small compared to the surface area of other drug delivery routes, such as the GI tract (350,000 cm.sup.2) and skin (20,000 cm.sup.2).
The contact time between the drug and the absorption surface is primarily controlled by the dissolution rate of the solid unit. Once the solid unit is dissolved, any drug solution not yet absorbed will be swallowed, thereby ending further OT drug absorption. Generally the time a solid unit can remain in the oral cavity is between 10 to 15 minutes, but this time period is quite variable and depends upon a number of factors. Some of the factors affecting the contact time are difficult to account for, such as how vigorously a patient will suck on the dosage form.
In addition to the difficulties presented by the oral cavity's unique environment, the physicochemical properties of the drug can present challenges and complications that affect oral transmucosal drug delivery. Primarily, the solubility, the dissolution rate, and the partition coefficient determine the extent to which a drug can be delivered via the oral mucosal tissue. Solubility and dissolution rate are key aspects in creating the concentration gradient, which is the driving force for drug delivery. Partition coefficient, on the other hand, acts like an amplifier, such that the drug delivery rate is directly proportional to the partition coefficient up to a point.
The solubility of a drug is an inherent characteristic of the drug in a particular solvent. The relative affinities of the solute molecules and the solid phases determine the solubility. In other words, the inter-molecular attractions between the solvent-solute and solute-solute molecules will largely determine solubility. The solubility of a drug is a specific thermodynamic property, that is, it describes the chemical state of the drug. Imbalance in a thermodynamic state will cause the change toward re-establishing a balance within the system. Because solubility is a specific thermodynamic quantity, any imbalance that causes a change away from solubility equilibrium will result in a change in the system toward re-establishing balance.
The partition coefficient is the concentration ratio of a drug between two phases. Partition coefficient is determined largely by the inherent properties of the drug. In the case of oral transmucosal delivery, the attraction of drug molecules between two phases on the solution/tissue interface determines the partition coefficient of the drug. As with solubility, partition coefficient is a thermodynamic property and any imbalance will cause a change toward re-establishing a balanced state.
The effectiveness of drug formulations is dependent upon the time frame imposed on the drug reaction. The dissolution rate of the drug, unlike the solubility and partition coefficient, is a kinetic property of a drug. An otherwise effective drug may have a dissolution rate which is acceptable for one delivery method but which is too slow for the particular time frame of another. For example the dissolution rate of a drug may be acceptable for GI delivery, but the dissolution rate may not be practical for oral transmucosal delivery. The time frame in oral transmucosal delivery is 10 to 15 minutes rather than 4 to 6 hours in the GI tract.
To a certain extent, the physicochemical properties of a drug can be manipulated by changing the surrounding environment. For example, the solubility of an ionizable drug can be greatly increased by changing the pH of the solution to a value at which the drug is in its ionized form. However, attempts to advantageously manipulate one particular physicochemical property can have a negative impact on another property. For instance, in designing a solid drug formulation, a pharmacist may attempt to increase the drug absorption by manipulating pH, but the altered pH negatively impacts other aspects of the formulation, such as the partition coefficient of the drug. Designing a solid, oral transmucosal formulation can be further complicated when a potentially effective solid formulation is unstable in storage and thereby rendered impractical for commercial use.
There are several ways drug designers attempt to increase solubility and dissolution rate. A common practice in the pharmaceutical industry is to use a co-solvent. Many drugs that are insoluble in aqueous media are more soluble in organic solvents. Formulations designed for intravenous injections often employ co-solvents to increase the solubility of drugs. However, solid dosage forms, by their nature, cannot be formed with co-solvents solubility.
Some relatively insoluble drugs can be combined with other molecules to form more soluble complexes. Cyclodextrins, for example, have been used in many formulations to increase the solubility of poorly soluble, hydrophobic drugs. Derivatized cyclodextrins are donut shaped molecules with a hydrophobic interior and hydrophilic exterior. Hydrophobic drugs can be sheltered inside the cyclodextrin cavity, and thus become soluble in the aqueous media.
One significant drawback to complexing is that once a drug molecule is complexed with another molecule, such as a hydrophobic drug inside a cyclodextrin, the drug is no longer a free molecule. In other words, complexing the drug allows the drug to go into solution, however, the complex often has poor absorption characteristics. This is often the case with cyclodextrin-complexed drugs. The drug alone may be capable of being absorbed, but due to its larger size, the drug/cyclodextrin complex is too large to be absorbed through the mucosa.
For weak acids or weak bases, which are ionizable, there is yet another way to manipulate the solubility and dissolution rate. The weak acid or weak base can react with base or acid, respectively, to form a salt. The ionized salt forms will almost always have higher solubilities and dissolution rates than the unionized forms. In many cases, they are also more stable chemically or physically. However, the ionized forms almost always have lower partition coefficients than the unionized forms, and therefore are less well absorbed by the oral mucosal tissue. Thus, converting the weak acid or base to an ionized form in order to increase solubility compromises absorption.
A common method of controlling the pH of the formulation is to use a buffer system. A buffer system consists of hydrogen ion donor(s) (acid) and conjugate hydrogen ion receiver(s) (base). An appropriate buffer system stabilizes the pH. However, optimizing the pH generally compromises the solubility and partition coefficient for oral transmucosal drug delivery.
It would be advantageous to design a solid oral transmucosal dosage that would allow for increased dissolution, solubility and stability of the drug and yet preserve the drug absorption rate. It would also be advantageous to provide a formulation concept and manufacturing processes for making solid dosage units embodying the foregoing attributes.